Comment on Lenz et al, page
In this multicenter, randomized prospective study of patients with advanced follicular lymphoma, autologous stem cell transplantation resulted in a doubling of progression-free survival at 5 years. Further follow-up is needed to establish a survival advantage, if any.
The role of autologous stem cell transplantation (ASCT) in follicular lymphoma has long been controversial, because of the lack of carefully controlled prospective data. The study of the German Lymphoma Study Group (GLSG) reported by Lenz and colleagues in this issue of Blood provides important new information and a much better definition of the benefits of ASCT. This study included patients younger than age 60 with advanced indolent lymphomas including follicular lymphoma, small lymphocytic lymphoma, and mantle cell lymphoma. The large majority of patients had follicular lymphoma and constitute the subject of the report. Standard treatment consisted of 8 cycles of cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) followed by interferon maintenance. Those patients randomized to the investigational arm received 6 cycles of CHOP, 1 cycle of Dexa-BEAM (dexa-methasone 3 × 8mg by mouth, days 1-10; BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] 60 mg/m2 intravenously, day 2; melphalan 20 mg/m2 intravenously, day 3; etoposide 75 mg/m2 intravenously, days 4-7; cytarabine 2 × 100 mg/m2 intravenously, days 4-7; and granulocyte-colony-stimulating factor [G-CSF] initiated on day 11) for stem cell mobilization, and ASCT with cyclophosphamide-total body irradiation (TBI) conditioning. Randomization occurred after the second course of induction therapy. (A second randomization, to an alternative induction regimen of mitoxantrone, chlorambucil, and prednisone [MCP], was stopped after preliminary analysis showed decreased stem cell mobilization with MCP).FIG1
PFS after high-dose radiochemotherapy followed by ASCT and IFN-α maintenance in follicular lymphoma. See the complete figure in the article beginning on page .
PFS after high-dose radiochemotherapy followed by ASCT and IFN-α maintenance in follicular lymphoma. See the complete figure in the article beginning on page .
Toxicities were as expected, with more myelosuppression, severe infections, gastrointestinal (GI) toxicity, and mucositis in the transplant arm and more muscle and bone pain and depression in the interferon arm. Treatment-related mortality was extremely low in both arms. The primary end point of the trial was progression-free survival (PFS), which was monitored continuously, so that the trial could be stopped as soon as significant superiority or, alternatively, futility of the transplant arm was documented. The results of the study in 240 evaluable patients and a median follow-up of longer than 4 years confirm superiority of ASCT over interferon maintenance. PFS is nearly doubled in the transplant arm (64.7% vs 33.3% at 5 years) and two thirds of patients randomized to transplant remain in remission at 5 years (Figure 1). The analysis focuses on those who completed induction therapy but an additional analysis of all randomized patients confirmed the results and ruled out any selection bias. The results are consistent with other recently reported randomized studies of ASCT in first or subsequent remission of follicular lymphoma.1-3
This does not mean that ASCT should now be accepted as the standard of care for patients with follicular lymphoma. First, more prolonged follow-up is needed to establish whether the advantage in PFS will also translate into a survival benefit. The high incidence of secondary myelodysplastic syndrome (MDS) in this and other studies of ASCT is of concern and could affect overall survival rates. Whether the excess risk for MDS is due to the conditioning regimen, the stem cell mobilization regimen, or even to a protective effect of interferon in the standard treatment arm remains an open question. Second, in a preliminary analysis of a more recent study, the GLSG demonstrated that addition of rituximab to CHOP yields comparable benefits to ASCT and may therefore represent a suitable alternative.4 Randomized trials of radioimmunochemotherapy (CHOP-tositu-momab) and of anti-idiotype vaccines are also under way. Their results may further alter therapeutic options. Thus, optimal treatment for follicular lymphoma remains to be defined.
Still, the availability of several new drugs and the completion of large studies with positive results are rapidly changing the paradigm of treatment for follicular lymphoma, long considered an incurable illness. If ASCT results in 5-year remission for two thirds of patients and CHOP-rituximab does the same, what about the combination? Only the future and more studies will tell.
